Fragile X Mental Retardation Protein and Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome: A Pilot Study
Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disa...
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| Published in | Brain sciences Vol. 12; no. 3; p. 314 |
|---|---|
| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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26.02.2022
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| Abstract | Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR5 expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR5 expression is increased in men with FXS to form the basis for improved clinical trials. Unexpectedly marked reductions in mGluR5 expression were observed in cortical and subcortical regions in men with FXS. Reduced mGluR5 expression throughout the living brains of men with FXS provides a clue to examine FMRP and mGluR5 expression in FXS. In order to develop the findings of our previous study and to strengthen the objective tools for future clinical trials of glutamatergic agents in FXS, we sought to assess the possible value of measuring both FMRP levels and mGluR5 expression in men with FXS. We aimed to show the value of measurement of FMRP levels and mGluR5 expression for the diagnosis and treatment of individuals with FXS and related conditions. We administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a specific mGluR5 radioligand for quantitative measurements of the density and the distribution of mGluR5s, to six men with the full mutation (FM) of FXS and to one man with allele size mosaicism for FXS (FXS-M). Utilizing the seven cortical and subcortical regions affected in neurodegenerative disorders as indicator variables, adjusted linear regression of mGluR5 expression and FMRP showed that mGluR5 expression was significantly reduced in the occipital cortex and the thalamus relative to baseline (anterior cingulate cortex) if FMRP levels are held constant (F(7,47) = 6.84, p < 0.001).These findings indicate the usefulness of cerebral mGluR5 expression measured by PET with [18F]FPEB and FMRP values in men with FXS and related conditions for assessments in community facilities within a hundred-mile radius of a production center with a cyclotron. These initial results of this pilot study advance our previous study regarding the measurement of mGluR5 expression by combining both FMRP levels and mGluR5 expression as tools for meaningful clinical trials of glutamatergic agents for men with FXS. We confirm the feasibility of this protocol as a valuable tool to measure FMRP levels and mGluR5 expression in clinical trials of individuals with FXS and related conditions and to provide the foundations to apply precision medicine to tailor treatment plans to the specific needs of individuals with FXS and related conditions. |
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| AbstractList | Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR5 expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR5 expression is increased in men with FXS to form the basis for improved clinical trials. Unexpectedly marked reductions in mGluR5 expression were observed in cortical and subcortical regions in men with FXS. Reduced mGluR5 expression throughout the living brains of men with FXS provides a clue to examine FMRP and mGluR5 expression in FXS. In order to develop the findings of our previous study and to strengthen the objective tools for future clinical trials of glutamatergic agents in FXS, we sought to assess the possible value of measuring both FMRP levels and mGluR5 expression in men with FXS. We aimed to show the value of measurement of FMRP levels and mGluR5 expression for the diagnosis and treatment of individuals with FXS and related conditions. We administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a specific mGluR5 radioligand for quantitative measurements of the density and the distribution of mGluR5s, to six men with the full mutation (FM) of FXS and to one man with allele size mosaicism for FXS (FXS-M). Utilizing the seven cortical and subcortical regions affected in neurodegenerative disorders as indicator variables, adjusted linear regression of mGluR5 expression and FMRP showed that mGluR5 expression was significantly reduced in the occipital cortex and the thalamus relative to baseline (anterior cingulate cortex) if FMRP levels are held constant (F(7,47) = 6.84, p < 0.001).These findings indicate the usefulness of cerebral mGluR5 expression measured by PET with [18F]FPEB and FMRP values in men with FXS and related conditions for assessments in community facilities within a hundred-mile radius of a production center with a cyclotron. These initial results of this pilot study advance our previous study regarding the measurement of mGluR5 expression by combining both FMRP levels and mGluR5 expression as tools for meaningful clinical trials of glutamatergic agents for men with FXS. We confirm the feasibility of this protocol as a valuable tool to measure FMRP levels and mGluR5 expression in clinical trials of individuals with FXS and related conditions and to provide the foundations to apply precision medicine to tailor treatment plans to the specific needs of individuals with FXS and related conditions. Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR5 expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR5 expression is increased in men with FXS to form the basis for improved clinical trials. Unexpectedly marked reductions in mGluR5 expression were observed in cortical and subcortical regions in men with FXS. Reduced mGluR5 expression throughout the living brains of men with FXS provides a clue to examine FMRP and mGluR5 expression in FXS. In order to develop the findings of our previous study and to strengthen the objective tools for future clinical trials of glutamatergic agents in FXS, we sought to assess the possible value of measuring both FMRP levels and mGluR5 expression in men with FXS. We aimed to show the value of measurement of FMRP levels and mGluR5 expression for the diagnosis and treatment of individuals with FXS and related conditions. We administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a specific mGluR5 radioligand for quantitative measurements of the density and the distribution of mGluR5s, to six men with the full mutation (FM) of FXS and to one man with allele size mosaicism for FXS (FXS-M). Utilizing the seven cortical and subcortical regions affected in neurodegenerative disorders as indicator variables, adjusted linear regression of mGluR5 expression and FMRP showed that mGluR5 expression was significantly reduced in the occipital cortex and the thalamus relative to baseline (anterior cingulate cortex) if FMRP levels are held constant (F(7,47) = 6.84, p < 0.001).These findings indicate the usefulness of cerebral mGluR5 expression measured by PET with [18F]FPEB and FMRP values in men with FXS and related conditions for assessments in community facilities within a hundred-mile radius of a production center with a cyclotron. These initial results of this pilot study advance our previous study regarding the measurement of mGluR5 expression by combining both FMRP levels and mGluR5 expression as tools for meaningful clinical trials of glutamatergic agents for men with FXS. We confirm the feasibility of this protocol as a valuable tool to measure FMRP levels and mGluR5 expression in clinical trials of individuals with FXS and related conditions and to provide the foundations to apply precision medicine to tailor treatment plans to the specific needs of individuals with FXS and related conditions.Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR5 expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR5 expression is increased in men with FXS to form the basis for improved clinical trials. Unexpectedly marked reductions in mGluR5 expression were observed in cortical and subcortical regions in men with FXS. Reduced mGluR5 expression throughout the living brains of men with FXS provides a clue to examine FMRP and mGluR5 expression in FXS. In order to develop the findings of our previous study and to strengthen the objective tools for future clinical trials of glutamatergic agents in FXS, we sought to assess the possible value of measuring both FMRP levels and mGluR5 expression in men with FXS. We aimed to show the value of measurement of FMRP levels and mGluR5 expression for the diagnosis and treatment of individuals with FXS and related conditions. We administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a specific mGluR5 radioligand for quantitative measurements of the density and the distribution of mGluR5s, to six men with the full mutation (FM) of FXS and to one man with allele size mosaicism for FXS (FXS-M). Utilizing the seven cortical and subcortical regions affected in neurodegenerative disorders as indicator variables, adjusted linear regression of mGluR5 expression and FMRP showed that mGluR5 expression was significantly reduced in the occipital cortex and the thalamus relative to baseline (anterior cingulate cortex) if FMRP levels are held constant (F(7,47) = 6.84, p < 0.001).These findings indicate the usefulness of cerebral mGluR5 expression measured by PET with [18F]FPEB and FMRP values in men with FXS and related conditions for assessments in community facilities within a hundred-mile radius of a production center with a cyclotron. These initial results of this pilot study advance our previous study regarding the measurement of mGluR5 expression by combining both FMRP levels and mGluR5 expression as tools for meaningful clinical trials of glutamatergic agents for men with FXS. We confirm the feasibility of this protocol as a valuable tool to measure FMRP levels and mGluR5 expression in clinical trials of individuals with FXS and related conditions and to provide the foundations to apply precision medicine to tailor treatment plans to the specific needs of individuals with FXS and related conditions. Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR 5 ) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR 5 expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR 5 expression is increased in men with FXS to form the basis for improved clinical trials. Unexpectedly marked reductions in mGluR 5 expression were observed in cortical and subcortical regions in men with FXS. Reduced mGluR 5 expression throughout the living brains of men with FXS provides a clue to examine FMRP and mGluR 5 expression in FXS. In order to develop the findings of our previous study and to strengthen the objective tools for future clinical trials of glutamatergic agents in FXS, we sought to assess the possible value of measuring both FMRP levels and mGluR 5 expression in men with FXS. We aimed to show the value of measurement of FMRP levels and mGluR 5 expression for the diagnosis and treatment of individuals with FXS and related conditions. We administered 3-[ 18 F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([ 18 F]FPEB), a specific mGluR 5 radioligand for quantitative measurements of the density and the distribution of mGluR 5 s, to six men with the full mutation (FM) of FXS and to one man with allele size mosaicism for FXS (FXS-M). Utilizing the seven cortical and subcortical regions affected in neurodegenerative disorders as indicator variables, adjusted linear regression of mGluR 5 expression and FMRP showed that mGluR 5 expression was significantly reduced in the occipital cortex and the thalamus relative to baseline (anterior cingulate cortex) if FMRP levels are held constant (F(7,47) = 6.84, p < 0.001).These findings indicate the usefulness of cerebral mGluR 5 expression measured by PET with [ 18 F]FPEB and FMRP values in men with FXS and related conditions for assessments in community facilities within a hundred-mile radius of a production center with a cyclotron. These initial results of this pilot study advance our previous study regarding the measurement of mGluR 5 expression by combining both FMRP levels and mGluR 5 expression as tools for meaningful clinical trials of glutamatergic agents for men with FXS. We confirm the feasibility of this protocol as a valuable tool to measure FMRP levels and mGluR 5 expression in clinical trials of individuals with FXS and related conditions and to provide the foundations to apply precision medicine to tailor treatment plans to the specific needs of individuals with FXS and related conditions. |
| Author | Goodman, Jack Alexander Berry-Kravis, Elizabeth M. Seibyl, John P. Brašić, James Robert Wong, Dean F. Budimirovic, Dejan B. Martin, Samuel D. Slifer, Keith Nandi, Ayon Jennings, Danna Russell, David S. Sedlak, Thomas Mathur, Anil Kumar Barret, Olivier |
| AuthorAffiliation | 12 Laboratory of Central Nervous System (CNS) Neuropsychopharmacology and Multimodal, Imaging (CNAMI), Mallinckrodt Institute of Radiology, Washington University, Saint Louis, MO 63110, USA 1 Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; anandi1@jh.edu (A.N.); smart149@jhu.edu (S.D.M.); tsedlak@jhmi.edu (T.S.); amathur4@jh.edu (A.K.M.); dfwong@wustl.edu (D.F.W.) 5 Denali Therapeutics, Inc., South San Francisco, CA 94080, USA 8 Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; slifer@kennedykrieger.org 11 Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA; elizabeth_berry-kravis@rush.edu 6 Laboratoire des Malad |
| AuthorAffiliation_xml | – name: 12 Laboratory of Central Nervous System (CNS) Neuropsychopharmacology and Multimodal, Imaging (CNAMI), Mallinckrodt Institute of Radiology, Washington University, Saint Louis, MO 63110, USA – name: 4 Invicro, New Haven, CT 06510, USA – name: 3 Institute for Neurodegenerative Disorders, New Haven, CT 06510, USA; drussell@invicro.com (D.S.R.); jennings@dnli.com (D.J.); olivier.barret@cea.fr (O.B.); jseibyl@invicro.com (J.P.S.) – name: 8 Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; slifer@kennedykrieger.org – name: 5 Denali Therapeutics, Inc., South San Francisco, CA 94080, USA – name: 1 Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; anandi1@jh.edu (A.N.); smart149@jhu.edu (S.D.M.); tsedlak@jhmi.edu (T.S.); amathur4@jh.edu (A.K.M.); dfwong@wustl.edu (D.F.W.) – name: 7 Department of Neuroscience, Zanvyl Krieger School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA – name: 2 Frank H. Netter MD School of Medicine, Quinnipiac University, North Haven, CT 06473, USA; jack.goodman@quinnipiac.edu – name: 13 Department of Psychiatry, Kennedy Krieger Institute, Baltimore, MD 21205, USA – name: 9 Department of Behavioral Psychology, Kennedy Krieger Institute, Baltimore, MD 21205, USA – name: 10 Department of Psychiatry and Behavioral Sciences-General Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA – name: 11 Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA; elizabeth_berry-kravis@rush.edu – name: 6 Laboratoire des Maladies Neurodégénératives, Molecular Imaging Research Center (MIRCen), Institut de Biologie François Jacob, Centre National de la Recherche Scientifique (CNRS), Commissariat à l’Énergie Atomique et aux Énergies Alternatives (CEA), Université Paris-Saclay, CEDEX, 92265 Fontenay-aux-Roses, France |
| Author_xml | – sequence: 1 givenname: James Robert orcidid: 0000-0002-3948-4853 surname: Brašić fullname: Brašić, James Robert – sequence: 2 givenname: Jack Alexander surname: Goodman fullname: Goodman, Jack Alexander – sequence: 3 givenname: Ayon surname: Nandi fullname: Nandi, Ayon – sequence: 4 givenname: David S. orcidid: 0000-0002-9105-2943 surname: Russell fullname: Russell, David S. – sequence: 5 givenname: Danna surname: Jennings fullname: Jennings, Danna – sequence: 6 givenname: Olivier surname: Barret fullname: Barret, Olivier – sequence: 7 givenname: Samuel D. surname: Martin fullname: Martin, Samuel D. – sequence: 8 givenname: Keith surname: Slifer fullname: Slifer, Keith – sequence: 9 givenname: Thomas surname: Sedlak fullname: Sedlak, Thomas – sequence: 10 givenname: Anil Kumar surname: Mathur fullname: Mathur, Anil Kumar – sequence: 11 givenname: John P. surname: Seibyl fullname: Seibyl, John P. – sequence: 12 givenname: Elizabeth M. surname: Berry-Kravis fullname: Berry-Kravis, Elizabeth M. – sequence: 13 givenname: Dean F. surname: Wong fullname: Wong, Dean F. – sequence: 14 givenname: Dejan B. orcidid: 0000-0001-7263-5134 surname: Budimirovic fullname: Budimirovic, Dejan B. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35326270$$D View this record in MEDLINE/PubMed https://cea.hal.science/cea-04471460$$DView record in HAL |
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| Keywords | radiotracer positron emission tomography (PET) linear regression fragile X mental retardation 1 gene (FMR1) correlation coefficient neurodevelopmental disorders temporal cortex anterior cingulate cortex neuroimaging thalamus |
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| SubjectTerms | Alzheimer's disease Animal models anterior cingulate cortex Autism Benzonitrile Clinical trials correlation coefficient Cortex (cingulate) FMR1 protein fragile X mental retardation 1 gene (FMR1) Fragile X syndrome Genotype & phenotype Glutamatergic transmission Glutamic acid receptors (metabotropic) Intellectual disabilities Kinases Life Sciences linear regression Mosaicism Neurodegenerative diseases neurodevelopmental disorders neuroimaging Occipital lobe Phenotypes Positron emission tomography Precision medicine Protein synthesis Proteins Thalamus Tomography |
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| Title | Fragile X Mental Retardation Protein and Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome: A Pilot Study |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/35326270 https://www.proquest.com/docview/2642343044 https://www.proquest.com/docview/2644008688 https://cea.hal.science/cea-04471460 https://pubmed.ncbi.nlm.nih.gov/PMC8946825 https://doaj.org/article/a1c24f10d046468782c1830dbc4bd8a5 |
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